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PMID: 8335693 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Osteoblasts are target cells for transformation in c-fos transgenic mice.

The Journal of cell biology ·Vol. 122 ·No. 3 ·1993-08-00 ·Pages 685-701

Grigoriadis AE, Schellander K, Wang ZQ, Wagner EF

Abstract

We have generated transgenic mice expressing the proto-oncogene c-fos from an H-2Kb class I MHC promoter as a tool to identify and isolate cell populations which are sensitive to altered levels of Fos protein. All homozygous H2-c-fosLTR mice develop osteosarcomas with a short latency period. This phenotype is specific for c-fos as transgenic mice expressing the fos- and jun-related genes, fosB and c-jun, from the same regulatory elements do not develop any pathology despite high expression in bone tissues. The c-fos transgene is not expressed during embryogenesis but is expressed after birth in bone tissues before the onset of tumor formation, specifically in putative preosteoblasts, bone-forming osteoblasts, osteocytes, as well as in osteoblastic cells present within the tumors. Primary and clonal cell lines established from c-fos-induced tumors expressed high levels of exogenous c-fos as well as the bone cell marker genes, type I collagen, alkaline phosphatase, and osteopontin/2ar. In contrast, osteocalcin/BGP expression was either low or absent. All cell lines were tumorigenic in vivo, some of which gave rise to osteosarcomas, expressing exogenous c-fos mRNA, and Fos protein in osteoblastic cells. Detailed analysis of one osteogenic cell line, P1, and several P1-derived clonal cell lines indicated that bone-forming osteoblastic cells were transformed by Fos. The regulation of osteocalcin/BGP and alkaline phosphatase gene expression by 1,25-dihydroxyvitamin D3 was abrogated in P1-derived clonal cells, whereas glucocorticoid responsiveness was unaltered. These results suggest that high levels of Fos perturb the normal growth control of osteoblastic cells and exert specific effects on the expression of the osteoblast phenotype.

Related Genes
c-fos
MeSH Terms
Animals Base Sequence Bone Neoplasms/genetics Calcitriol/pharmacology Cell Transformation, Neoplastic Dexamethasone/pharmacology Gene Expression Genes, fos Mice Mice, Transgenic Molecular Sequence Data Osteoblasts/cytology,metabolism Osteogenesis Osteosarcoma/genetics Phenotype Proto-Oncogene Proteins c-fos/genetics,metabolism Tumor Cells, Cultured
Chemicals
Proto-Oncogene Proteins c-fos Dexamethasone Calcitriol
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Grigoriadis A E
Research Institute of Molecular Pathology, Vienna, Austria.
Schellander K
Wang Z Q
Wagner E F
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.122.3.685
Published
1993-08-00
Pages
685-701
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2119671
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.122.3.685 PMC Full Text View journal details
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